3'-Deoxykanamycin A, which was first prepared semisynthetically by H. Umezawa et al. (Japanese Patent Publication No. 33109/76; U.S. Pat. No. 3929761), is known to exhibit a remarkably improved antibacterial activity against a variety of kanamycin A-resistant bacteria, as compared with kanamycin A. The 1-N-.alpha.-hydroxy-.omega.-aminoacylated derivative of 3'-deoxykanamycin A has a markedly improved antibacterial activity against the kanamycin A-resistant bacteria (Japanese Patent KOKAI No. 127045/76; U.S. Pat. No. 4104372). In particular, such a 1-N-aminoacylated derivative of 3'-deoxykanamycin A of which the 1-amino group has been acylated with (S)-4-amino-2-hydroxybutyryl group, that is, 3'-deoxyamikacin exhibits a higher antibacterial activity against any of the kanamycin-resistant bacteria, as compared with amikacin, that is, 1-N-[(S)-4-amino-2-hydroxybutyryl]-kanamycin A which has been already used clinically. Accordingly, 3'-deoxykanamycin A is a useful substance by itself and it is a valuable substance also as a starting material for the preparation of other valuable semi-synthetic anti-bacterial substances.
Kanamycin A contains a hydroxyl group in the 2'-position in addition to the 3'- and 4'-hydroxyl groups in the molecule, and in this respect kanamycin A is different from neamine, kanamycin B and ribostamycin which contain an amino group in the 2'-position and of which the 3'-deoxygenation has been reported before. For this reason, it was difficult to protect preferentially the 2'- and 4'-hydroxyl groups amongst the neighboring 2',3'- and 4'-hydroxyl groups of kanamycin A with a known hydroxyl-protecting group, while leaving the 3'-hydroxyl group unprotected. Besides, another some reasons have resulted in a delay in development of the process for 3'-deoxygenation of kanamycin A. Thus, kanamycin A cannot be 3'-deoxygenated by known methods for 3'-deoxygenation which were successfully applicable to the selective removal of the 3'-hydroxyl group from neamine, kanamycin B and ribostamycin and which are usually performed by sulfonylating the 3'-hydroxyl group with a known sulfonylating agent, replacing the resultant 3'-sulfonyloxy group by a halo group or thiol anion group and then removing reductively the halo or thiol anion group to achieve the 3'-deoxygenation. This is mainly owing to that it is hard to effect the step of replacing the 3'-sulfonyloxy group by a halo or thiol anion group because of steric hindrance or electrostatic repulsion which is induced by the presence of the 1'-.alpha.-glucoside linkage in the kanamycin A molecule.
As the methods for synthesis of 3'-deoxykanamycin A, there may be mentioned the method of U.S. Pat. No. 3,929,761or Japanese Patent Publication No. 33109/76 in which 6-azido-2,4-di-O-benzyl-3,6-dideoxy-.alpha.-D-ribohexopyranosyl chloride is condensed with 6-O-(2-O-benzyl-3-deoxy-3-ethoxycarbonylamino-4,6-O-isopropylidene)-N,N'-d iethoxycarbonyl-2-deoxystreptamine and the resulting condensation product is treated in some steps for removing therefrom the amino-protecting groups and the hydroxyl-protecting groups to afford 3'-deoxykanamycin A. Recently, there has been proposed a method of pending Japanese patent application No. 139,798/79; U.S. patent application Ser. No. 198,612 and U.K. patent application No. 8035016 which includes two alternative procedures. Its first procedure comprises imidazolylthiocarbonylation of 3'- and 2"-hydroxyl group of 4",6"-O-cyclohexylidene-4'-0:6'-N-carbonyl-5,2'-O-isopropylidene-1,3,3"-tr i-N-tosylkanamycin A, preferential removal of 3'-imidazolylthiocarbonyloxy group with tributyltin hydride for the 3'-deoxygenation, followed by removal of 2"-O-imidazolylthiocarbonyl group with aqueous ammonia, removal of N-tosyl groups with alkali or alkaline earth metal in liquid ammonia, hydrolytic fission of 4',6'-cyclic carbamate ring and concurrent removal of 5,2'-O-isopropylidene group and 4",6"-O-cyclohexylidene group, and the second procedure comprises selective acetylation of 2"-hydroxyl group of said protected kanamycin A derivative with acetyl chloride in pyridine, trifluoromethanesulfonylation of 3'-hydroxyl group, followed by concurrent removal of 3'-trifluoromethanesulfonyloxy group and N-tosyl groups with alkali metal in liquid ammonia, removal of 2"-O-acetyl group concurrently to hydrolytic fission of 4',6'-cyclic carbamate, and hydrolytic removal of the 5,2'-O-isopropylidene and 4",6"-O-cyclohexylidene groups.
However, the prior art method of the U.S. Pat. No. 3,929,761 is inefficient and gives in a poor yield the condensation product from the two starting compounds employed, and the further method of the pending Japanese patent application No. 139,798/79 or U.S. patent application Ser. No. 198,612 needs expensive reagents and dangerous operations. All the above-mentioned methods are therefore in need to be further modified so that they are much adaptable for commercial practice.
In these circumstances, we, the present inventors, researched extensively in an attempt to provide a new and more efficient process for the production of 3'-deoxy-kanamycin A which is performable in an easy, inexpensive and safe way to give the desired product in a favorably high yield.
As a result, we have now found that when a 2',2"-di-O-acyl-3'-O-sulfonyl-tetra-N-protected derivative of kanamycin A of formula (I): ##STR3## wherein R, W and X have the same meanings as defined above is treated with a base such as an alkali metal alcoholate in a lower alkanol, 2',3'- and 3',4'-epoxidations take place concurrently to removal of the 2'- and 2"-acyl groups, and that when the resultant reaction solution containing the epoxidized derivatives so produced (which are herein referred to also as the anhydro derivatives) is subjected either to the reduction with hydrogen in the presence of a known hydrogenation catalyst such as Raney nickel or platinum group metal catalyst or to the reduction with sodium borohydride, the 3'-deoxygenated derivative of kanamycin A can preferentially be produced from said anhydro derivatives but a 2'-deoxy-3'-epi derivative and 4'-deoxy-3'-epi derivative of kanamycin A which were expected to be formed as by-products actually cannot be formed, contrary to our expectation. Thus, we have established a new route for the preparation of 3'-deoxykanamycin A from a protected kanamycin A derivative which is performable in a facile way with a relatively small number of steps.